Homeostasis in the gastrointestinal tract is characterized by a balanced relationship between the host and indigenous microbes, collectively referred to as the microbiota. Paneth cells are an intestinal epithelial cell type tha plays a significant role in shaping the microbiota by secreting antimicrobial peptides, including alpha- defensins. Alpha-defensins have been shown to have a significant role in determining the composition of the intestinal microbiota. Therefore, I hypothesize that the intestinal microbial ecology is, in part, defined by alpha- defensin resistance. Analyses from fecal metagenomic library screening with intestinal alpha-defensins are proposed to identify novel genes conferring resistance mechanisms. In an initial pilot analysis, candidate resistance genes in Faecalibacterium prausnitzii have been identified. These studies aim to provide an explanation for why certain microbes are enriched or present in the intestinal tract. Bacteria in the Bacteroidaceae family are present in the intestinal tract, and select members are suggested to be resistant to intestinal alpha-defensins. However, the candidate genes for resistance mechanisms have not been defined. My laboratory has established that members in the Bacteroidaceae family induce disease in a murine model system of inflammatory bowel disease (IBD). Using this model, I can functionally test the relevance of alpha-defensin resistance to disease. Moreover, my laboratory has a panel of Bacteroidaceae isolates and a mutant that induce different levels of disease in this model system. I will compare these isolates to determine whether Bacteroidaceae have specific mechanisms for alpha-defensin resistance and whether defensin resistance can define the disease-inducing potential of a microbe. Results from this study may have implications for human IBD, which is estimated to affect about a million people in the United States. Microbial contributions to IBD pathogenesis are recognized. Thus, understanding alpha-defensin resistance in the intestinal microbiota during homeostasis and a possible link between defensin resistance and disease-inducing potential, may aid in the identification of candidate opportunistic pathogens for IBD and other intestinal diseases.